Lead investigator: Susan Gilmour, PhD
Collaborator: Otto Phanstiel, PhD, University of Central Florida

Solid tumors have an enormous appetite for polyamines, a class of nutrients made in the body but also acquired in the diet. While all cells use polyamines, tumor cells require much higher levels and therefore must scavenge them by strongly activating a polyamine-uptake system. Blocking polyamines can arrest the growth and survival of tumor cells, but an effective strategy to selectively attack tumor cells by blocking their polyamine uptake process has been elusive.

Recent work by two leaders in the field has now led to the discovery of drug-based strategies to target the upregulated polyamine-transport system in tumors. In preclinical studies, these strategies safely and effectively kill tumor cells, either directly, with polyamine-conjugated cytotoxic drugs, or indirectly, by reversing local tumoral immunosuppression and activating effective anti-tumor immunity. Proof of concept studies have demonstrated general anti-tumor efficacy in several experimental tumor systems, including melanoma, breast, ovarian, colorectal and pancreas cancers. Thus, the discovery offers general utility in cancer treatment, including in combination with molecular targeted drugs or immunotherapy.

Technology description

Researchers at LIMR and the University of Central Florida (UCF) have synthesized and characterized novel proprietary small molecules that function as bioactive polyamine-transport inhibitors (PTIs) or polyamine-cancer drug conjugates (“Trojan Horse” targeted drugs). Both classes include compounds with the potential for immediate clinical translation.

PTIs attack tumors by blocking polyamine uptake by tumor cells and other cell types present in the tumor microenvironment. Strikingly, LIMR researchers have found that combination treatment with a PTI to block polyamine uptake with an FDA-approved drug that blocks polyamine synthesis (termed polyamine-based therapy, or PBT) activates a tumor-specific immune response that can eradicate tumors. Mechanistic investigations suggest that the PTI exerts its potent immune-activating effects by relieving an arginase-polyamine metabolic pathway that tumors use to suppress the immune system. As a result, poorly immunogenic metastatic tumors that are resistant to immunotherapy, such as anti-PD-1 therapy, become responsive when co-treated with PBT.

“Trojan Horse” targeted drugs kill tumor cells by turning their voracious polyamine uptake against themselves. Specifically, these compounds include a polyamine moiety conjugated to a cytotoxic drug known to kill cancer cells. Since polyamine transporters are more active in cancer cells than normal cells, the greater uptake of the conjugate by cancer cells selectively kills them. This targeting principle has been shown to be safe and efficacious in preclinical testing at clinically relevant concentrations.

Business opportunity

PTIs represent a new class of immunometabolic adjuvants, an area of intense current interest in the dynamic field of immune-oncology. This field is broadening from its initial clinical successes in melanoma, moving into lung, renal, urothelial and other cancers. “Trojan Horse” approaches have been validated in clinic, but general strategies to address solid tumors as a group via polyamine-targeting strategies have not been developed.

Focusing only on melanoma— where about 50 percent of patients remain largely untreatable despite recent advances—about 91,000 cases are diagnosed in the U.S. yearly.

The global market for melanoma therapeutics was valued at U.S. $4.2 billion in 2016, with an expected compound annual growth rate of 11.21 percent from 2018 through 2025, according to the market research firm Grand View Research.

Intellectual property position

  1. Composition of matter and use of polyamine transport inhibitors, U.S. Patent No. 9730902 (issued Aug 15, 2017).
  2. Composition of matter and use of polyamine-drug conjugates, U.S. Patent No. 9926260 (issued Mar 27, 2018).
  3. Use of PTI and DFMO as immunomodulatory therapy – patent pending.
  4. Collaboration agreement in place between LIMR and UCF with sharing of intellectual property.

Relevant publications

Hayes CS, Shicora AC, Keough MP, Snook AE, Burns MR and Gilmour SK. (2014). Polyamine-blocking therapy reverses immunosuppression in the tumor microenvironment. Cancer Immunol Res. 3:274-85.

Alexander ET, Minton A, Peters MC, Phanstiel IV O and Gilmour SK. (2017). novel polyamine blockade therapy activates an anti-tumor immune response. Oncotarget. 8:84140-52.

Peters MC, Minton A, Phanstiel IV O and Gilmour SK. (2018). A Novel Polyamine-targeted therapy for BRAF mutant melanoma tumors. Med Sci. 6:3.